Project Summary/Abstract: Lafora disease (LD) is a glycogen metabolic disorder that manifests itself as neurodegenerative epilepsy. A pathological hallmark of LD is the accumulation of abnormal insoluble glycogen that resembles plant starch in various organs including brain. LD occurs due to autosomal recessive mutations in genes encoding proteins laforin and malin. Laforin is a dual-specificity phosphatase and malin is an E3 ubiquitin ligase. Multiple studies in LD field have shown that laforin functions as a phosphatase for glycogen. Malin forms a functional complex with laforin and malin alone or the laforin- malin complex is known to ubiquitinate multiple proteins involved in glycogen metabolism. Hormones insulin and glucagon tightly control blood glucose homeostasis by their effect on glucose transport and storage. In type-2 diabetes, defects in insulin responsiveness leads to a state called insulin resistance. Few studies in LD research have looked at insulin response in LD knockout animals. One study found that laforin knockout mice had enhanced insulin response by PI3K-Akt pathway that led to increased glucose transport and glycogen synthesis. However, another study, with better-matched genetic background for the wildtype and knockout mice, observed that insulin response was normal in both laforin and malin knockout mice. In addition, a study using knockdown of laforin and malin in cell culture showed that glucose transporters translocate to cell membrane in cells lacking laforin or malin and that these cells have higher glucose uptake. LD patients die in the second decade of life and therefore a pathophysiological correlation of LD and diabetes is absent. Moreover, ubiquitin posttranslational modification of glycogen-metabolic proteins has not been studied in diabetes pathophysiology. Our proposal will study the effect of hormones and nutrients on novel glycogen metabolic proteins- laforin and malin in physiology and diabetes pathophysiology. Any defects in the expression, signaling, and function of these proteins in diabetes will provide us with targets to regulate glucose storage. The proposal is highly relevant in our understanding of glycogen metabolic disorders and diabetes mellitus.